In our SBIR Phase 1 research program we discovered two novel ROR?t inverse agonist lead series and showed efficacy in two animal models of inflammatory bowel disease (IBD). IBD is a significant health burden reducing the quality of life of 1.4 million people in the United States alone. Th17 cells are a lineage of T helper cells that have recently been identified as critical mediators of the immunopathology of several human inflammatory disease states, including IBD. The orphan nuclear receptor ROR?t has been shown to be the master controller of the differentiation of Th17 cells. ROR?t knockout animals are highly resistant to several autoimmune diseases. In healthy people, Th17 cells are chiefly located in the lamina propria of the small intestine. In IBD patients, this compartmentalization breaks down and Th17 cells migrate and expand in number at inflamed tissue sites throughout the gut. Antagonism of the transcriptional activity of ROR?t blocks the differentiation of CD4+ T-cells into the Th17 cell lineage. Thus, ROR?t inverse agonists reduce the Th17 cell population at sites of inflammation. Th17 cells secrete large quantities of IL-17A, IL-17F, IL-22, TNF-? and other inflammatory cytokines. ROR?t drives the production of these cytokines and it has been demonstrated that ROR?t inverse agonists reduce the secretion of these cytokines from pre-existing Th17 cells. Therefore, small molecule inverse agonists of ROR?t will effectively treat IBD by reducing the Th17 cell population and IL-17A/F production. We discovered novel and potent ROR?t inverse agonists that functionally block the ex vivo differentiation of human Th17 cells. Importantly, we demonstrate in two IBD animal efficacy models that our most advanced lead compound significantly attenuates the disease. Analyses of the proximal target biomarkers shows that the compound effects are occurring via the expected mechanism-of-action, inverse agonism of ROR?t. Based on the success of the Phase 1 SBIR work, we propose the following aims: (1) optimize the pharmacological properties and oral bioavailability of novel ROR?t inverse agonists using our proprietary BindingSIGHTS drug design platform to guide a medicinal chemistry/testing cycle; (2) determine the ex vivo T-cell functional activity of ROR?t inverse agonists on human Th17, Th1, Th2 and Treg cells; (3) evaluate the therapeutic efficacy of orally bioavailable ROR?t inverse agonists in animal models of IBD; (4) evaluate the safety/toxicity of the most advanced compounds to nominate candidates for Investigational New Drug (IND) enabling studies. Together, these studies will provide orally bioavailable therapeutics for IBD that will facilitate subsequent human clinical trials.